Lipoprotein-Associated Phospholipase A2 (Lp-PLA2), also previously known in the art as Platelet Activating Factor Acetly Hydrolase (PAF acetyl hydrolase) is a member of the super family of phospholipase A2 enzymes that are involved in hydrolysis of lipoprotein lipids or phospholipids. It is secreted by several cells that play a major role in the systemic inflammatory response to injury, including lymphocytes, monocytes, macrophage, T Lymphocytes and mast cells.
During the conversion of LDL to its oxidised form, Lp-PLA2 is responsible for hydrolysing the sn-2 ester of oxidatively modified phosphatidylcholine to give lysophosphatidylcholine and an oxidatively modified fatty acid. Lp-PLA2 hydrolyzes the sn2 position of a truncated phospholipid associated with oxidized LDL. As a result, there is a generation of 2 inflammatory cell homing mediators (non-esterfied fatty acids (NEFA) and LYSO PC). Both NEFA and LYSO PCs are chematractants for circulating monocytes, play a role in the activation of macrophages and increase oxidative stress as well as affecting the functional and the immediate responses of T lymphocytes. Lp-PLA2 is bound in humans and pigs to the LDL molecule via lipoprotein B, and once in the arterial wall the oxidized LDL is susceptible to hydrolysis by Lp-PLA2.
Both of these products of Lp-PLA2 action are potent chemoattractants for circulating monocytes. As such, this enzyme is thought to be responsible for the accumulation of cells loaded with cholesterol ester in the arteries, causing the characteristic ‘fatty streak’ associated with the early stages of atherosclerosis, and inhibition of the Lp-PLA2 enzyme may be useful in preventing the build up of this fatty streak (by inhibition of the formation of lysophosphatidylcholine), and useful in the treatment of atherosclerosis.
In addition, it is proposed that Lp-PLA2 plays a direct role in LDL oxidation. This is due to the poly unsaturated fatty acid-derived lipid peroxide products of Lp-PLA2 action contributing to and enhancing the overall oxidative process. In keeping with this idea, Lp-PLA2 inhibitors inhibit LDL oxidation. Lp-PLA2 inhibitors may therefore have a general application in any disorder that involves lipid peroxidation in conjunction with the enzyme activity and/or activated inflammatory responses, for example in addition to conditions such as atherosclerosis and diabetes other conditions such as rheumatoid arthritis, myocardial infarction and reperfusion injury.
The skin is the largest organ of the human body. This applies to exterior surface, as it covers the body, appearing to have the largest surface area of all the organs. Moreover, it applies to weight, as it weighs more than any single internal organ, accounting for about 15 percent of body weight. For the average adult human, the skin has a surface area of between 1.5-2.0 square meters, most of it is between 2-3 mm thick. The average square inch of skin holds 650 sweat glands, 20 blood vessels, 60,000 melanocytes, and more than a thousand nerve endings.
As an organ, the skin is an integumentary system made up of multiple layers of epithelial tissues: epidermal, dermis, and hypodermis that guard underlying muscles and organs. As the interface with the surroundings, it plays the most important role in protecting against pathogens, by providing a waterproofing and barrier layer to infection. Its other main functions are insulation and temperature regulation, sensation and vitamin D and B synthesis. Minor excretion of urea and the absorption of oxygen and medicine are also achieved via the skin. Hence the skin is considered one of the most important parts of the body.
When the integrity of the skin is compromised, such as in abrasion or a cut, there is a discontinuity of the multiple layers of epithelial layers and the protective function of the skin is thus locally lost. The human body elicits a localized wound healing response primarily aimed at plugging the epithelial discontinuity and prevent invasion of pathogens. The wound healing response involves increasing blood flow to the wound, mobilizing numerous immune cells (phagocytic macrophages) and inflammatory responses to clear away any pathogens and cell debris, mobilizing fibroblast cells to wound site and secreting extracellular matrix, and seal the wound by regenerating the dermal and epidermal layers.
Sometimes, this wound healing response is impaired or impeded due to various medical conditions and/or repeating trauma, and combinations thereof such that the wound remains as an open sore or ulcer in the skin. This open sore is vulnerable to infection by pathogens in the surrounding area. The skin ulcer may enlarge from infection and aberrant inflammation. Pus (dead immune cells, skin cells, and infectious agents) accumulate in the cavity of the skin ulcer to form an abscess. Abscesses in most parts of the body rarely heal themselves, so prompt medical attention is indicated at the first suspicion of an abscess.
As the skin is the first line of defense against any pathogens in our surroundings, having a chronic ulcer represents a very serious and dangerous medical situation that require immediate and aggressive treatment, and failure to address the problem in a timely manner can lead to dire consequences such as gangrene, lost of appendages resulting from amputation, septicemia, and even death.
Chronic skin wounds are a far-too-common problem in people with diabetes, circulatory problems, cancer, immune system disorders, neurological disorders or limited mobility who are thus either wheelchair bound or bedridden. The limited mobility may be from paralysis due to injuries or disease, or birth defects such as cerebral palsy and spina bifida. Chronic skin ulcer is the major contributing factor to the death of the famous actor Christopher Reeve who was paralyzed in a horse riding accident. The prevalence of skin ulcers can be as high as 60 percent in quadriplegic patients and 66 percent in elderly patients admitted for femoral fracture (See “The Agency for Health Care Policy and Research” Clinical Practice Guideline Number 3, AHCPR Pub. No. 92-0047). For diabetic patients, 15% will develop skin ulcers that are highly susceptible to infection at least once in their lifetime. Indeed, 85% of diabetic amputations performed annually are preceded by ulcers Glover J. L., et. al., 1997, Adv. Wound Care 10:33-38.
It is estimated that in the United States of America alone, there are between 5-7 million people afflicted with chronic skin ulcers (Petrie N, et. al, 2003, Surgical Clinics of North America 83(3):194-9). Annually in America, the total direct cost of chronic wounds, including wound diagnostic and surgical procedures, pharmaceuticals, wound closure devices and hospital and physician charges, amounts to an estimated $20 billion (Frykberg R, et. al., 2000, J Foot Ankle Surg 39(5 Suppl):1-60; Harding K, et. al., 2002, BMJ 324(7330):160-3). The indirect costs of chronic wounds, such as lost work time and impaired quality of life, are not included in this estimate and are difficult to quantify, but can be contemplated to be substantial.
Currently chronic wound management includes medications such as anti-bacterial and anti-fungal drugs, thrombolytic agent or clot-busting agents such as tissue plasminogen activator (tPA), the use of compression bandages, bioengineered skin substitutes (Cultivated Epidermal Allografts), electrical stimulations, advanced drug delivery systems such as iontophoresis-based transdermal delivery system, localized delivery of materials that repair tissue such as platelet derived and autologous growth factor, granulocyte-macrophage colony stimulating factor (G-M CSF), and mesoglycan, negative pressure wound therapy and ultrasound. However, despite a multi-disciplinary approach to treat and promote the healing of chronic skin ulcers with aggressive management of infection and improve blood circulation, chronic skin ulcers continue to be a major clinical problem. Most of the time, doctors have had no way to determine early on which wounds might require these advanced and expensive procedures. Therefore there is still a need for new advancement in the treatment as well as prevention of skin ulcers in people that fall within the high risk population of developing chronic skin ulcers. In addition, there is a pressing need for new advancement in the prevention of recurring episodes of skin ulcers among people at risk.